The epithelial cells lining the lumenal side of the gastrointestinal tract (GTT) are a major barrier to drug delivery following oral administration. However, there are four recognized transport pathways which can be exploited to facilitate drug delivery and transport: the transcellular, paracellular, carrier-mediated and transcytotic transport pathways. The ability of a conventional drug, peptide, protein, macromolecule, nanoparticulate system or microparticulate system to interact with one of these transport pathways may result in increased delivery of that drug or particle from the GIT to the underlying circulation.
M-cells are antigen sampling cells that are found in the epithelium of the gut-associated lymphoid tissue, or Peyer's Patch. The transcytotic capacity of M-cells and the downstream processing of the antigen sampled would suggest that targeting vaccines to M-cells would enhance oral immunization (Foster et al., 15 Vaccine 546-71 (1998)). However, to date, no human M-cell marker has been identified as a target for delivery of vaccines and/or other drugs through the M-cell route.
In U.S. Pat. No. 6,117,632 to O'Mahony, one of the present inventors disclosed a method of identifying peptides which permit or facilitate the transport of an active agent through human or animal epithelial tissue. This method uses in vivo phage display screening to identify ligands.
U.S. Pat. No. 6,060,082 to Chen et al. discloses modified polymerized liposomes that contain a molecule or ligand on their surfaces in order to target the liposomes to a specific site or cell type for oral/mucosal drug delivery. Also disclosed is an embodiment in which the liposomes are modified with carbohydrate moities or lectins that specifically target M-cells or Peyer's Patches in mice. However, this reference only teaches transport of liposomes.
Other approaches include: drug delivery through the epithelium by a carrier molecule selected from transferrin receptor ligands conjugated to an active agent and a transport enhancing agent (U.S. Pat. No. 5,254,342 to Shen et al.); and coupling the antigen to ligands that bind the FcRn receptor. (U.S. Pat. No. 6,030,613 to Blumberg et al.).
All references cited herein are incorporated herein by reference in their entireties.
Thus, there still exists a need for M-cell and/or Peyer's Patch specific ligands that are particularly effective in transporting drugs, including drug-loaded nanoparticles and microparticles, or bacterial or viral carries coding for vaccines into or across a human or animal intestinal epithelium.